3-beta-acyloxy-5, 7, 9 (11)-pregnatrien-12, 20-diones



Patented Oct. 13, 1953 UNITED STATES 3-BETA-ACYLOXY-5,7,9 (11)PREGNATRIEN- 12,20-DIONES Robert H. Levin, A Vern McIntosh, Jr., andGeorge B. Spero, Kalamazoo, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Michigan No Drawing. Application May.24, 1951, Serial No. 228,134

Claims. 1

The present invention relates toS-beta-acyloxy-5,7,9(11)-pregnatrien-12,20-diones, and to processes fortheir production.

This application is a continuation-in-part of our copending applicationSerial No. 184,702, filed September 13, 1950, now Patent No. 2,623,043,to which reference is made also for the preparation of the startingcompounds referred to in this specification.

The 3-beta-acyloxy-5,7,9(l1)-pregnatrien-l2,- 20-diones which are thepreferred embodiment of this invention are represented by the followingformula:

r CH? 2? in which Ac is an acyl radical or the residue of an organiccarboxylic acid, especially those aliphatic carboxylic acids containingfrom 1 to 8 carbon atoms, inclusive, per molecule.

The principal object of the present invention is to provide novelcompounds which are useful in the preparation of steroid compoundscontaining an oxygen atom at carbon atom 11 in the steroid nucleus.Another object of the present invention is to provide a process for theproduction of these new compounds. Other objects and advantages of theinvention, some of which are referred to hereinafter, will be apparentto those skilled in the art to which the invention pertains.

The compounds of the present invention are useful in the preparation ofsteroid compounds having an oxygen atom attached to carbon atom 11. Suchoxygen-containing steroids are of particular interest because of thebiological activity of the adrenal cortical hormones and certain knownderivatives thereof, which differ markedly in their biological effectsfrom steroids that lack oxygen in their constitution. Because of thepresent acute shortage of adrenal cortical hormones and the lack ofmethods for their synthesis, the compounds of the present inventionofier promise as starting materials for the production ofoxygen-containing steroids possessing desirable biological activity.

Compounds of the present invention which are of particular interest arethose compounds conforming to the foregoing general formula and in whichAcO represents the radical resulting from the esterification of the3-hydroxyl group of the (Cl. EGO-397.4)

steroid with a carboxylic acid containing up to and including 8 carbonatoms. Such acids include formic, acetic, propionic, butyric, valeric,hexanoic, heptanoic, octanoic, succinic, glutaric, cyclopentanoic,cyclohexanoic, benzoic, toluic, and the like; the lower aliphatic acidsof this group are preferred embodiments of the invention. The acids maycontain other substituents, such as halogen, alkyl and methoxy radicals,which are nonreactive with the reagents used in the methods describedherein for the preparation of the compounds of the invention.

The compounds of the present invention are usually colorless crystallinesolids. The steroid nucleus of the compounds of the present inventionmay be partially or completely saturated by hydrogenation. The compoundsare also convertible to 3-hydroxy and 3-keto derivatives.

The starting compounds from which the compounds of the present inventionare prepared are adducts of l2-keto-3-beta-acyloxy-5,7,9(11)-pregnatrien-ZO-ones with maleic acid and anhydride, having the generalformula:

the first of which represents that derived from maleic anhydride whilethe second represents that derived from maleic acid.

The preparation of the compounds of this invention, which is describedin detail in our copending applications Serial 184,702, filed September13, 1950, and Serial No. 228,133 filed concurrently herewith, consistsessentially of the folleaving (alternative procedures are also describedin our said copending applications):

1. Dehydroergosterol is converted to an adduct with maleic anhydride ormaleic acid [I-I. Hcnigmann, Annalen 508, 89-98 (1934) l.

2. The adduct of dehydroergosterol is es-terified by reaction, forexample, with benzoyl chloride, acetyl chloride or formic acid.

3. The resulting adduct of the B-beta-acyloxydehydroergosterol isozonized and then reduced in acid solution with zinc dust to obtain anadduct of a 3beta-acyloxybisnor-5,7,9(11)-cholatrien- 22-al. (Seeapplication of Robert H. Levin, Serial No. 111,100, filed August 18,1949, now Patent No. 2,260,337, for details.)

4. An enol ester of the resulting3beta-acyloxybisnor-5,7,9(11)-cholatrien-22-al adduct is prepared andozonized to the adduct of a 3-betaacy1oxy-5,'7,9(11)-pregnatrien-20-one.

5. The resulting adduct of the 3-be-ta-acyloxy-5.7,9(11)-pregnatrien-20-one is reacted with N-bromosuccinimide orbromine to produce an adduct of a 3-beta-acyloxy-12-bromo-5,7,9(11)-pregnatrien-20-one.

6. The adduct of the 3-beta-acyloxy-12-bromo- 5,7,9(11)-pregnatrien-20-one, on reaction with silver nitrate as described in ourcopending application Serial No. 228.131, filed May 24, 1951, yields theadduct of 3-betaacyloxy-12-hydroxy- 5,7,!)(11)-pregnatrien-20-one. Othermethods for the preparation of the 12-hydroxy compound are described inour copending application Serial No. 228,132 filed on even dateherewith.

'7. The adduct of the3-beta-acyloxy-12-hydroxy-5,'7,9(1l)-pregnatrien-20-one is then oxidizedwith chromic acid, as described in our copending application Serial No.228,133, to obtain the desired adduct of the 3-beta-acyloxy- 5,7,9 (11)-pregnatrien-12,20-dine.

In accordance with the process of our invention, maleic acid and maleicanhydride adducts of 3-acyloxy-5,'7,9(11)-pregnatrien-12,20-diones ofthis invention are converted to trienes, namely 3-acyloxy-5,7,9 (11)-pregnatrien-12,20-di0nes, having double bonds at the 5(6), 7(8) and9(11) positions, and the formula:

CHa

wherein Ac has the significance hereinbefore specified. The removal ofthe maleic acid or maleic anhydride radical is efiected by a pyrolysisreaction which consists essentially in heating the maleic acid or maleicanhydride adduct of ne 3-acyloxy-5,7,9(11) -pregnatrienl2,20-dione inthe presence of an organic amine at a temperature of approximately 100to approximately 225 degrees centigrade, with or without the presence ofan organic solvent, and thereafter isolating the product triene. It isnot necessary to isolate the adducts from reaction mixtures in whichthey are formed in order to efiect the removal of the adduct radical inaccordance with such pyrolysis processes, since the entire reactionmixture or crude product may be treated. The

desired triene can be obtained in a high degree of purity and inexcellent yields.

Amines which can be used in this pyrolysis process include: secondaryaliphatic amines such as dimethylamine, diethylamine, dipropylamine,dibutylamine, diamylamine, dioctylamine; tertiary aliphatic amines suchas trimethylamine, triamylamine, methyldioctylamine, methyldiethylamine;secondary and tertiary cycloaliphatic amines such asN-methylcyclohexylamine, N,N- dimethylcyclohexylamine,N,N-diethylcyclohexylamine; secondary and tertiary heterocyclic aminessuch as pyrrolidine, Nmethylmorpholine, N-ethylpyrrolidine, morpholine,piperidine, N-rnethylpiperidine, 2-methylpiperidine,1,2-dimethylpiperidine, 1,2,-trimethylpiperidine, 2,4,6-trimethylpiperidine, 1-ethyl-2,4,6-trimethylpiperidine; aromaticheterocyclic amines such as pyridine, picoline, lutidine, collidine,quinoline, quinaldine, lepidine, B-methylquinoline; secondary andtertiary carbocyclic aromatic amines such as N-methylaniline,Nethylaniline, N-butylaniline, N-benzylaniline, N,N-dimethylaniline,N,N-diethylaniline, N,N-dibutylaniline, N,N-dibenzylaniline,N-methyltoluidine, N,N-diethyltoluidine, N-ethylxylidine,N,N-dimethylxylidine; substituted aliphatic amines such asdiethylaminoethanol, dibutylaminoethanol, N-pyrrolidylethanol,N-piperidylethanol; substituted aromatic amines such asortho-methoXy-N,N-dimethylaniline, para-ethoxy-N,N-diethylaniline,para-chloro-N,N-dimethylaniline, para-bromo- N ,N -diethylaniline,para-fluoro-N,N-dibutylaniline, N,N-dimethylmesidine (N,Ndimethyl-2,4,6-trimethylaniline) secondary and tertiary aralkyl amines such asmethylbenzylamine, dimethylbenzylamine, propylbenzylamine,diisopropylphenethylamine, diethylphenylisopropylamine; and primaryamines such as butylamine, hexylamine, octylamine, cyclohexylamine,aniline, toluidine, xylidine and the like.

The process comprises heating the selected 3-acyloxy-12,20-dione maleicacid or maleic anhydride adduct to a temperature between approximatelyand approximately 225 degrees centigrade, preferably between and 200degrees centigrade, in the presence of an organic amine, removing excessamine, and recovering the product triene. The time required for thereaction is usually from approximately 1 to approximately 8 hours,depending upon such factors as the particular steroid adduct beingtreated, the amine employed, and the temperature of reaction.Ordinarily, a reaction period of approximately 4 hours is entirelysatisfactory, although, at lower temperatures, a more extended periodmay be employed to advantage. The employment of pressure may in somecases be advantageous, although it is in most cases preferred to conductthe pyrolysis reaction at atmospheric pressure. After completion of thereaction, the triene product can be recovered in conventional manner,such as by evaporation of solvent in vacuo, redissolving the residue inan organic solvent, e. g., methanol, diluting with water, extractingwith ether, washing the solution untilneutral, drying, evaporating todryness, chromatographing over an alumina column, and recrystallizingfrom an organic solvent, if desired.

ErampZe.3-beta-aceto$y-5,7,9 (11) pregnatrien-12,20-dione Three grams ofthe maleic anhydride adduct of 3 beta acetoxy 5,7,9(l1) pregnatrien-12,20-dione, melting point, 232-235 degrees centigrade, prepared asdescribed in our copending application Serial No. 228,183, was mixedwith 30 milliliters of N,N-dimethylbenzylamine and heated at refluxtemperature for 6 hours, the compound going into solution as soon asheat was applied. The solvent was then removed at a subatmosphericpressure and the residue dissolved in 50 milliliters of methanol,diluted with 300 milliliters of water, and extracted with fourZ5-milliliter portions of ether. The ether solution was washedsuccessively with 200 milliliters of cold 2-percent hydrochloric acidsolution, 200 milliliters l-percent sodium carbonate solution, andwater. After drying the solution and evaporating it to dryness, 2.01grams of residue was obtained. This residue was purified bychromatography over alumina, resulting in a yield of 0.62 gram ofcrystalline 3-beta-acetoxv-5,'7,9 (11) -pregnatrien- 12,20-dione,melting point 150-158 degrees centigrade. Recrystallization from alcoholraised the melting point to 160-162 degrees centigrade. Analysis:

Analysis.

Calculated for 023112 0 C, 74.97; H, 7.66 Found 75.13 7.31 74.79 7.60

The 3 acyloxy 5,7,9(11) pregnatrien- 12,20-diones are convertible to3-hydroxy-5,'7,9- (11) pregnatrien 12,20 dione having the formula:

by saponiflcation of the 3-acyloxy compound in an alcohol, e. g.,methanol or dioxane, as well as similar solvents, using at least oneequivalent of an aqueous solution of a base. The product is isolated bydrowning out with water or in other conventional manner, and may bepurified by recrystallization from an organic solvent, if desired. Thesecompounds and methods for their production are described more fully andclaimed in our copending application Serial No. 231,904, now Patent No.2,628,240.

The 3 hydroxy 5,7,9(11) pregnatrien- 12,20-dione is in turn convertibleto the triketone, 4,7,9(1l) -pregnatrien-3,12,20-trione, having theformula:

by dissolving the starting 3-hydroxy compound in a suitable organicsolvent, e. g., toluene, adding cyclohexanone and aluminum isopropoxide,and refluxing the solution for from 3 to 8 hours. The reaction productmay then be poured into a dilute aqueous solution of ammonium chloride,

and the product triketone extracted with ether. The ether solution maythen be washed successively with dilute hydrochloric acid and water,dried, and the solution evaporated to dryness. The residue may becrystallized from an organic solvent to give a more highly purifiedtriketone product, if desired. This triketone, and a method for itsproduction are described more fully and claimed in our copendingapplication Serial No. 264,648, filed January 2, 1952.

The trienes of the present invention may be hydrogenated in steps toproduce compounds in which the steroid nucleus is partially orcompletely saturated. Thus, when 3-beta-acetoxy-5,7,9(l1)-pregnatriene-12,20-dione is hydrogenated at a superatmosphericpressure in the presence of a -palladium catalyst (for example, 10 percent palladium on calcium carbonate or 20 per cent palladium oncharcoal), 3 beta acetoxy- 8(9) -pregnene-12,20-dione is the productwhen the reduction is stopped after absorption of 2 molecularproportions of AcO is formed.

Although the foregoing specification is directed particularly to thepyrolysis of the maleic anhydride adduct of3beta-acetoxy-5,'7,9(ID-pregnatrien-l2,20-dione to produce3-beta-acetoxy- 5,7,9(11)-pregnatrien-12,20-dione, it is to beunderstood that maleic acid aclducts and both maleic acid and maleicanhydride adducts of other 3 beta-acyloxy 5,7,9 (11) pregnatriene-12,20-diones and may be similarly treated to remove the adduct radical.Accordingly, the invention is to be limited solely to the compounds andprocesses specified in the claims.

We claim:

1. A 3 beta-acyloxy 5,7,!)(11) pregnatrien 12,20-dione represented bythe formula:

oral/5 I I 2. 3 beta acetoxy-5,7,9(ll) pregnatrien-- 12,20-dione. g

3. A process for the production ofa3-betaacyloXy-5,7,9(ll)-pregnatrien-12,20-dione which comprises heatingan adduct of the group consisting of maleic acid and maleic anhydrideadducts of 3-beta-acyloxy-5,7,9(1l) pregnatrien- 12,20-diones, whereinthe acyloxy group contains up to and including eight carbon atoms, inthe presence of an organic base, and subsequently recovering the3-beta-acyloxy-5F ,9 11) -pregnatrien-12,20-dione.

4. A process as defined in claim 3 in which the temperature of heatingis maintained between approximately 100 and approximately 225 degreesCentigrade.

5. A process for the production of 3-betaacetoXy-5,7,9 (11) -pregnatrien12,20-dione which comprises heating the maleic anhydride adduct of3-beta-acetoxy 5,7,9(11)-pregnatrien-12,20-

dione in the presence of N,N-dimethylbenzylamine at a temperaturebetween approximately 175 and approximately 200 degrees Centigrade, andsubsequently recovering the 3-beta-acetoxy- 5,7,9 (11)-pregnatrien-12,20-dione.

ROBERT H. LEVIN. A VERN MCINTOSH, JR. GEORGE B. SPERO.

References C ted in the file of this patent UNITED STATES PATENTS NumberName Date 2,447,325 Gallagher Aug. 17, 1948 FOREIGN PATENTS NumberCountry Date 594,878 Great Britain Nov. 21, 1947

1. 3-BETA-ACYLOXY-5,7,9(11)-PREGNATRIEN12,20-DIONE REPRESENTED BY THEFORMULA: